A Phase I Study of [225Ac]-AZD2284 in Patients with Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria

• Main Inclusion Criteria:
• • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• • Histologically confirmed diagnosis of adenocarcinoma of the prostate without strong clinical suspicion of majority neuroendocrine differentiation.
• • Must have had prior bilateral orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L).
• • At least one metastatic lesion present on baseline Computed Tomography (CT), Magnetic Resonance Imaging (MRI), or bone scan obtained ≤ 28 days prior to the first dose of Investigational Medicinal Product (IMP). Participants may have non-measurable lesions including bone only metastases.
• • Adequate organ function
• • Part A only: Metastatic prostate cancer considered to be stable or progressing metastatic castration resistant prostate cancer (mCRPC).
• • Part B only: Progressing mCRPC defined as meeting at least one of following documented criteria -
• a) Serum/plasma PSA progression
• b) Soft-tissue progression
• c) Progression of bone disease
• • Part B Dose Escalation: Previously treated with at least 2 prior lines of systemic anti-cancer therapy for mCRPC. Prior lines must include:
• a) At least 1 androgen receptor pathway inhibitor (ARPI)
• b) A poly (adp-ribose) polymerase (PARP) inhibitor for participants with known BRCA mutation
• c) A checkpoint inhibitor for participants with known microsatellite instability-high (MSI-H), deficient mismatch pair (dMMR), or tumor mutational burden (TMB) ≥ 10 mut/Mb
• • Part B Dose Expansion: Previously treated with at least 1 prior line of systemic anti-cancer therapy for mCRPC. Prior lines must include:
• (a) At least 1 ARPI
• (b) A PARP inhibitor for participants with known BRCA mutation per local practice, unless ineligible per Investigator decision.
• (c) A checkpoint inhibitor for participants with known MSI-H, dMMR, or TMB ≥ 10 mut/Mb.
• (d) No previous cytotoxic chemotherapy for CRPC. Taxanes for metastatic hormone sensitive prostate cancer (mHSPC) is acceptable if the last cycle Day 1 was > 12 months before first study treatment.
• (e) Previous treatment with prostate specific membrane antigen radioligand therapy (PSMA-RLT) or Radium-223 is allowed but not required. Participants who have had prior radiation therapy, including therapeutic radiopharmaceuticals, external bean radiation therapy (EBRT), and/or brachytherapy are eligible, subject to satisfying all other inclusion/exclusion criteria. Therapeutic radiopharmaceuticals will be considered a prior line of systemic therapy.
• Main Exclusion Criteria:
• • Treatment with any radiopharmaceutical within 6 weeks of the first dose of Investigational Medicinal Product (IMP).
• • Radiation therapy (RT) or external beam radiation therapy (EBRT) within 28 days prior to the first dose and all RT-related events have not recovered to Grade ≤ 1.
• • Administration of any systemic cytotoxic or investigational therapy ≤ 28 days of the first dose of IMP or 5 half-lives, whichever is shorter.
• • All prior treatment-related adverse events must have resolved to Grade ≤ 1.
• • Concurrent severe and/or uncontrolled illness not related to cancer and/or social situation that would limit compliance with study requirements.
• • Known or suspected allergies or contraindications to any of the investigational drugs or any component of the investigational drug formulation.
• • Clinically relevant proteinuria
• • Diffuse and intense osseous radiotracer uptake on bone scintigraphy or PSMA imaging characteristic of a superscan.
• • Chronic corticosteroid use greater than 10 mg prednisone equivalent daily.